Basic nitro derivatives of 9 aminoacridine and process of preparing the same



Patented Nov. 25, 1 930 \N UNHTE STATES fPAIN N'rm-me HEINRICH JENSCH, on HooHs'r-oN-rHE-Mnm, AND OTTO nrsnnn'on IiOFNEIM QN-T'HE- TAUNUS, GERMANY, ASSIGNORS TO WINTER-OP CHEMICAL COMPANY, me, on NEW YORK, N. Y A CORPORATION on NEW YonK N a i v 1 BASIC NITRo nnnliverlvns or e aMINoAcnInINE AND rnocnss on PREPARING THE SAME V N No Drawing. Application filed January e, 928, Seria1-No. 24=5,04(, and in Germany Jamar 11 1927.

The present invention relates to basic nitro-derivatives of 9-am1noacr1d1ne and a N process of preparing-the same. N

We have found that all of the hitherto known organic compounds of chemotherapeutic value are surpassed as regards their bactericidal efficacy by new acridine derivatives being. nitro-acridine derivatives substitn'ted 9position bythe group NHR-gand in 10 one of the other positions of the nuceliis by a basic residue. The new compounds thus ob-L Ntainablecorrespon'd to the general formula:

least one R for the nitro group and another R5 fora basic residue, the remaining R representing hydrogen, halogen, or a n1tro-,' alkyl or alkoxy group.

By the tern1=basic residue? 1s to be understood in the sense off-the foregoing formula to the acridlne r ng for instancethrongh the siich radicals contain at least one aliphatically'bound N-a'tom and which may be linked medium of oxygen (in the manner :of an ether) or ofnitrogen (inthe manner ofan amine): for of carbon (in the manner of a i The said newcompounds are obtained by subjecting nitro-Q-chloracridines, containing atlealst one ofthe above defined basic residues, to reaction with ammonia or a primary amine. Instead of nltro-9-chloracridines there Nmay also be used the corresponding nitr Q-alkoxyaCridines and nitro-9-aryloxyacridines for the" preparation of the basic nitroacridines in question, or the transformation may be efi-ected with the nitro-9-alkoXy-N acridines or the nitro-9 aryloxyacridines whlc-h are obtained as intermediateproducts.

The reaction takes place in all cases,in presence or also in absence of a solvent. 1 N

he 'following examples illustrate our in vention, but they are notintended to limit it thereto, the parts being by weight: 1 1. 2 ,8 diethylamino ethoXy -6- nitro 9- aminoacridine. l p

r NO: Byheating 24 parts of potassium 2-chloro L-nitrobenzoate and 21 parts ofpara-aminophenol B diethylainino ethyl-ether in an amylalcoholicsolution with the addition of some natural copper C (a very pure, finely divided form of copper), 4-B-diethylaminoethoXy 5 nitro-diphenylamine-2-carboxylic acid is obtained inthe form of brownish crystals decomposing at 226 CI VVhentreated according to Ullnianns process which is de num chloride and phosphorus pentachloii'idc N the latter acid yields Q-fl-diethylaminoethoXy-G-nitroacri;done which by treating it with phosphoriis pentachloride is trans formed into 2-fi-Cll6t-l1Ylfill1lllO-6tllOX:Y-6-11ltro-9-chloracridineforming brownish needles with a golden luster and melting at159 C;

160 C. Ammonia introduced, While stirringylnto asolution of 2-,8-diethyla i ethoxy 6 nitro 9 chloracridine in twice its weight of phenol.) The temperature of the mixture is" gradually raised to C, to C; by supplyingheat fromcutside and maintained at these .degreesfor 15 minutes,

While continuing the introduction of ammonla. The formation of the basic nitro-derivatives of 9-aininoacridine takes place according to the following equations:

momncmomo V H] P0013 T \NOI (b) (HbC2)zN.OH .CH .O

A1013: l; No2

crystalline powder is obtained constituting the dihydrochloride of the 2-,8-diethylaminoethoXy-(S-nitro-9-aminoacridine with a content of 3 molecules of water of crystallization. It melts at 265 0., and is readily soluble in water. The addition of sodium acetate to the aqueous solution does not cause any precipitation of the base; but adding caustic soda solution thereto, the base is precipitated in the form of a red crystalline powder melting at 237 C. to 238 C.

2. 2-B-diethylamino -ethoi;y 6-nitro-9-isoamylaminoacridine.

me. on;

H2 It: (HCz)2NHzC.HzC0

N NOa 18.6 parts of 2(,B-diethylaminoethoxy)-6- nitro-9-chloracridine, 5 parts of isoaniylamine, 55 parts of phenol are gradually heated, while stirring, to 120 C. and the mass is maintained at this temperature for minutes. After cooling, alcoholic hydrochloric acid, containing 2.5 parts of HCl, is added to the reaction product and the hydrochloride oi the new compound is precipitated by means of ether, filtered by suction, thoroughly washed with ether and dried. It forms a brown crystalline powder which is very readily soluble in water, alcohol and chloroform, insoluble in benzene, ether and carbon disulfide. Its solution in water shows a neutral reaction and yields with sodium acetate no precipitate; with sodium carbonate or caustic soda solution the base obtained as a red substance.

' 3. 2 [3 piperidinoethoxy-6-nitro-9-aminoacridine.

By heating 12 parts of potassium 2-chloro- 4:nitro-benzoate and 11 parts of 4t-aminophenol ,8 piperidinoethylether (melting point 56 (1., boiling point 200 C. under 9 mm. pressure) in an amylalcoholic solution with the addition of a small quantity of natural copper C, -fl-piperidinoethoXy-5-ni tro-diphenylamine-2-carboXylic acid is obtained melting at 225 C. with decomposition. By effecting the closure of the acridone-ring according to Ullmanns method and treating the product with phosphorus pentachloride, 2-B-piperidinoethoxy-6-nitro- 9-chloracridine is obtained which forum brownish-yellow crystals melting at 175 C. to 176 C. The reaction with ammonia in phenol occurs in the same manner as in EX- ample 1. Alcohol of per cent. strength is used for recrystallizing the crude salt. The 2- [3 piperidinoethoxy-o-nitro-9-aminoacridine dihydrochloride crystallizes with two molecules of water of crystallization into brown needles. It is readily soluble. in water; on addition of sodium acetate the solution as- ,sumes a darkercoloration, and on-addition ,of ammonia the base is precipitated in the form of reddish-brown flakes melting at 243 C. V 4. 4 ,8 diethylaminoethoxy-6nitro 9-ami noacridine.

2 B diethylaminoethoxy-5-nitrodiphenylamine-2-carboXylic acid is obtained by subjecting 2-chlor-4-nitrobenzoic acid, po-

tassium, carbonate and 2-aminophenol-B-diethylaminoethylether '(boilingpoint 152 C.

C as a catalyst.

under 7 mm. pressure) to'reaction in amylalcohol with the addition of natural copper It forms a reddish brown crystalline powder decomposing at 213 C. to

214 C. When treated with phosphorus pentachloride and aluminium chloride, this acid yields the 4-13-diethylamin0ethoXy-6- nitroacridone which can further be transformed by means of phosphorus pentachlo' ride into 4-B-diethylamino-6-nitro-9-chloracridine melting at 127 C. to 128 C.

5 parts of thelast named chloracridine, 1O

a parts ofphenol and 1 part of Very finely pul- 0:: m In a Verized ammonium chloride are mixed and heated, while st1rr1ng,the temperature being maintained for two hours at 120 C. to 130; C. There are then added thereto parts of alcohol whereby crystals are precipitated. After having allowed the mass to stand for some time in the cold, itfis filtered by suction, washed with alcohol and recrystallized from alcohol of 80 per cent. strength. The

product thus obtained constitutes the 4-B-diethylaminoethoxy-G-nitro 9 aminoacridine dihydrochloride containing two molecules of waterof crystallization and melting at 27 2.

C. to 273 C. The base when precipitated from the solution of the salt in water by means of causticsoda solution,is a red powder which assumes a dark reddish-brown coloration on being dried on the water bath.

5. 2 B-diethylaminoethyl-6 nitro 9-aniinoacridine. 1 By the reaction of e (4-nitrophenyl) -ethyl chloride with diethylamine and subsequent reduction by means of iron, there is obtained ,8 (4-aminophenyl) -ethyl-diethylamine of the formula nmO-omommomm in the form of a colorless and nearlyodorless liquid boiling at 143 C. to 146C. under 7 mm. pressure.

By causing this amine to react with potassium 2-chlor-4-nitrobenzoate in an amylalcoholic solutionin the presence of copper, 4

diethylaminoethyl-5 -nitro-diphenylamine 2 carboxylic acid is obtained which forms a brilliant red crystalline powder decomposing at 240C. to 245 2-,diethylaminoethyl-6- nitro-acridone is prepared according to Ullcausing sodium 4-acetaminophenolate to react with trimethylenechlorobromide, there is obtained 4 aceta1ninophenolchlorpowder decomposing at propylether whichnielts at 113to 115 C.

This compound transformed by means of diethylamine into 4-acetamino phenol ynr ethylaminopropylether which, on being split 7 is i i up with hydrochloric acid, yields the 4'-amino phenol y diethylaminopropylether in the 7 form of a colorless and odorless oil boiling at 17 0 C. to 171 C. under 5 mm. pressure. By heating this substance with anJequimoled ular quantityot potassium 2-chlor-4-nitroben;

zoate in amylacohol in the presence of copper,

4- diethylaminopropyloxy AiS-nitro dephenylamine-2-carboxylic acid is obtained which is transformed by way of the 2 -diethyla1n ino-propyloxy-G-nitroacridone into the 2-y diethylaminopropyloxy-6-nitro 9 chloracridine. 3 parts of this chloracridine areheated with lpart of ammonium chloride and 9 parts of phenol, while stirring, to 12.5 C. to 180, C. and kept at this temperature lt'or2 hours. After cooling, 30 parts acetone are added thereto, the crystalline mag ma is filtered by suction,thoroughly washed Withace tone and dried. dissolving the substance in water. and precipitating the filtered solu tion by means of caustic soda solution, the

2- -diethylaminopropyloxy-GgnitrO-Q-amii1o acridine isseparated asa brilliant brick-red powder. In orderto transform it into the di hydrochloride; lpart of the base is dissolved in 3 parts by Volume of double normal hydrochloric acid by heating on the water bath and 6 parts by Volume of alcohol are added thereto, whereuponthe salt;crystallizes into thin yellow needles. It is filtered by suction and washed with alcohol. It contains in this form water of crystallization which it gives off when dried at C.

The nitro-acridines substituted in 9 position by halogen, which are named in the following claims as starting materials, are equivalents of nitr'o-9-alkoxyor nitro-S-aryloxyacridines which are formed from the nitro-9- halogen-acridines by treating them with so- (linm alcoholate or phenol. By the term radical containing at least one aliphatically bound nitrogen atom are to be understood such substituents being linked to the acridine ring, through the medium of oxygen (in the manner of an ether) or of nitrogen (in the manner oi an amine) or of carbon (in the manner of the CC linkage), and which contain at least one nitrogen atom not directly linked to the acridino ring.

lVe claim:

1. The process for preparing therapeutically active basic nitro derivatives of 9-aminoacridine, which consists in causing compounds of the formula: NI-LR wherein R stands for hydrogen or alkyl to act upon nitro-acridines substituted in 9-position by halogen and substituted at another C-atom of the acridine ring by a radical containing at least one aliphatically bound N-atom.

2. The process for preparing therapeutically active basic nitro derivatives of 9-aminoacridine, which consists in causing compounds of the formula: NH R wherein R stands for hydrogen or alkyl to act upon nitro-9-chloracridine substituted at a C-atom of the acridine ring by a radical containing at least one aliphatically bound N-atom.

3. As new products, the derivatives of nitro-9-aminoacridines of the following general formula:

HVRI

(C2115) 2N. CH GU20 being a red crystalline powder melting at 237 C. to 238 C. and forming a dihydrochloride which is a brownish crystalline powtures.

HEINRICH JENSCH.

OTTO EISLEB. 

